IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v548y2017i7669d10.1038_nature23477.html
   My bibliography  Save this article

Identification of essential genes for cancer immunotherapy

Author

Listed:
  • Shashank J. Patel

    (National Cancer Institute, National Institutes of Health (NIH)
    NIH-Georgetown University Graduate Partnership Program, Georgetown University Medical School)

  • Neville E. Sanjana

    (New York Genome Center
    New York University)

  • Rigel J. Kishton

    (National Cancer Institute, National Institutes of Health (NIH))

  • Arash Eidizadeh

    (National Cancer Institute, National Institutes of Health (NIH))

  • Suman K. Vodnala

    (National Cancer Institute, National Institutes of Health (NIH))

  • Maggie Cam

    (National Cancer Institute, National Institutes of Health (NIH))

  • Jared J. Gartner

    (National Cancer Institute, National Institutes of Health (NIH))

  • Li Jia

    (National Cancer Institute, National Institutes of Health (NIH))

  • Seth M. Steinberg

    (National Cancer Institute, National Institutes of Health (NIH))

  • Tori N. Yamamoto

    (National Cancer Institute, National Institutes of Health (NIH)
    Immunology Graduate Group, University of Pennsylvania)

  • Anand S. Merchant

    (National Cancer Institute, National Institutes of Health (NIH))

  • Gautam U. Mehta

    (National Cancer Institute, National Institutes of Health (NIH))

  • Anna Chichura

    (National Cancer Institute, National Institutes of Health (NIH))

  • Ophir Shalem

    (University of Pennsylvania)

  • Eric Tran

    (National Cancer Institute, National Institutes of Health (NIH))

  • Robert Eil

    (National Cancer Institute, National Institutes of Health (NIH))

  • Madhusudhanan Sukumar

    (National Cancer Institute, National Institutes of Health (NIH))

  • Eva Perez Guijarro

    (National Cancer Institute, National Institutes of Health (NIH))

  • Chi-Ping Day

    (National Cancer Institute, National Institutes of Health (NIH))

  • Paul Robbins

    (National Cancer Institute, National Institutes of Health (NIH))

  • Steve Feldman

    (National Cancer Institute, National Institutes of Health (NIH))

  • Glenn Merlino

    (National Cancer Institute, National Institutes of Health (NIH))

  • Feng Zhang

    (Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research, Massachusetts Institute of Technology)

  • Nicholas P. Restifo

    (National Cancer Institute, National Institutes of Health (NIH)
    Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH))

Abstract

Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic loss-of-function mutations involved in resistance to these therapies, by using a genome-scale CRISPR–Cas9 library that consisted of around 123,000 single-guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8+ T cells. The genes that were most enriched in the screen have key roles in antigen presentation and interferon-γ signalling, and correlate with cytolytic activity in patient tumours from The Cancer Genome Atlas. Among the genes validated using different cancer cell lines and antigens, we identified multiple loss-of-function mutations in APLNR, encoding the apelin receptor, in patient tumours that were refractory to immunotherapy. We show that APLNR interacts with JAK1, modulating interferon-γ responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models. Our results link the loss of essential genes for the effector function of CD8+ T cells with the resistance or non-responsiveness of cancer to immunotherapies.

Suggested Citation

  • Shashank J. Patel & Neville E. Sanjana & Rigel J. Kishton & Arash Eidizadeh & Suman K. Vodnala & Maggie Cam & Jared J. Gartner & Li Jia & Seth M. Steinberg & Tori N. Yamamoto & Anand S. Merchant & Gau, 2017. "Identification of essential genes for cancer immunotherapy," Nature, Nature, vol. 548(7669), pages 537-542, August.
  • Handle: RePEc:nat:nature:v:548:y:2017:i:7669:d:10.1038_nature23477
    DOI: 10.1038/nature23477
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/nature23477
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/nature23477?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Marcel P. Trefny & Nicole Kirchhammer & Priska Auf der Maur & Marina Natoli & Dominic Schmid & Markus Germann & Laura Fernandez Rodriguez & Petra Herzig & Jonas Lötscher & Maryam Akrami & Jane C. Stin, 2023. "Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    2. Stefanie Hiltbrunner & Lena Cords & Sabrina Kasser & Sandra N. Freiberger & Susanne Kreutzer & Nora C. Toussaint & Linda Grob & Isabelle Opitz & Michael Messerli & Martin Zoche & Alex Soltermann & Mar, 2023. "Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Irineos Papakyriacou & Ginte Kutkaite & Marta Rúbies Bedós & Divya Nagarajan & Liam P. Alford & Michael P. Menden & Yumeng Mao, 2024. "Loss of NEDD8 in cancer cells causes vulnerability to immune checkpoint blockade in triple-negative breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Nina Frey & Luigi Tortola & David Egli & Sharan Janjuha & Tanja Rothgangl & Kim Fabiano Marquart & Franziska Ampenberger & Manfred Kopf & Gerald Schwank, 2022. "Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Dzana Dervovic & Ahmad A. Malik & Edward L. Y. Chen & Masahiro Narimatsu & Nina Adler & Somaieh Afiuni-Zadeh & Dagmar Krenbek & Sebastien Martinez & Ricky Tsai & Jonathan Boucher & Jacob M. Berman & K, 2023. "In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    6. Louise A. Baldwin & Nenad Bartonicek & Jessica Yang & Sunny Z. Wu & Niantao Deng & Daniel L. Roden & Chia-Ling Chan & Ghamdan Al-Eryani & Damien J. Zanker & Belinda S. Parker & Alexander Swarbrick & S, 2022. "DNA barcoding reveals ongoing immunoediting of clonal cancer populations during metastatic progression and immunotherapy response," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    7. Christos Miliotis & Yuling Ma & Xanthi-Lida Katopodi & Dimitra Karagkouni & Eleni Kanata & Kaia Mattioli & Nikolas Kalavros & Yered H. Pita-Juárez & Felipe Batalini & Varune R. Ramnarine & Shivani Nan, 2024. "Determinants of gastric cancer immune escape identified from non-coding immune-landscape quantitative trait loci," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    8. Dario Zimmerli & Chiara S. Brambillasca & Francien Talens & Jinhyuk Bhin & Renske Linstra & Lou Romanens & Arkajyoti Bhattacharya & Stacey E. P. Joosten & Ana Moises Silva & Nuno Padrao & Max D. Welle, 2022. "MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    9. Su Yin Lim & Elena Shklovskaya & Jenny H. Lee & Bernadette Pedersen & Ashleigh Stewart & Zizhen Ming & Mal Irvine & Brindha Shivalingam & Robyn P. M. Saw & Alexander M. Menzies & Matteo S. Carlino & R, 2023. "The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    10. Julia Joung & Paul C. Kirchgatterer & Ankita Singh & Jang H. Cho & Suchita P. Nety & Rebecca C. Larson & Rhiannon K. Macrae & Rebecca Deasy & Yuen-Yi Tseng & Marcela V. Maus & Feng Zhang, 2022. "CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    11. Zoran Z. Gajic & Aditya Deshpande & Mateusz Legut & Marcin Imieliński & Neville E. Sanjana, 2022. "Recurrent somatic mutations as predictors of immunotherapy response," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    12. Hongxing Shen & Fengyuan Huang & Xiangmin Zhang & Oluwagbemiga A. Ojo & Yuebin Li & Hoa Quang Trummell & Joshua C. Anderson & John Fiveash & Markus Bredel & Eddy S. Yang & Christopher D. Willey & Zech, 2022. "Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    13. Edward Jenkins & Markus Körbel & Caitlin O’Brien-Ball & James McColl & Kevin Y. Chen & Mateusz Kotowski & Jane Humphrey & Anna H. Lippert & Heather Brouwer & Ana Mafalda Santos & Steven F. Lee & Simon, 2023. "Antigen discrimination by T cells relies on size-constrained microvillar contact," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    14. Tian-Yu Song & Min Long & Hai-Xin Zhao & Miao-Wen Zou & Hong-Jie Fan & Yang Liu & Chen-Lu Geng & Min-Fang Song & Yu-Feng Liu & Jun-Yi Chen & Yu-Lin Yang & Wen-Rong Zhou & Da-Wei Huang & Bo Peng & Zhen, 2021. "Tumor evolution selectively inactivates the core microRNA machinery for immune evasion," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    15. Davide Bernareggi & Qi Xie & Briana C. Prager & Jiyoung Yun & Luisjesus S. Cruz & Timothy V. Pham & William Kim & Xiqing Lee & Michael Coffey & Cristina Zalfa & Pardis Azmoon & Huang Zhu & Pablo Tamay, 2022. "CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    16. Martin Lauss & Bengt Phung & Troels Holz Borch & Katja Harbst & Kamila Kaminska & Anna Ebbesson & Ingrid Hedenfalk & Joan Yuan & Kari Nielsen & Christian Ingvar & Ana Carneiro & Karolin Isaksson & Kri, 2024. "Molecular patterns of resistance to immune checkpoint blockade in melanoma," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:548:y:2017:i:7669:d:10.1038_nature23477. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.